Hydroxypropyl methyl cellulose acetate succinate and method for producing the same

ABSTRACT

There is provided a method for producing hydroxypropyl methyl cellulose acetate succinate (HPMCAS), including an esterification step of reacting hydroxypropyl methyl cellulose with an acetylating agent and a succinoylating agent in the presence of an aliphatic carboxylic acid in a kneader reactor equipped with two or more stirring blades rotating around their own axes and orbitally revolving, to obtain a reaction product solution containing HPMCAS; a precipitation step of precipitating the HPMCAS by mixing the reaction product solution with water to obtain a suspension of the precipitated HPMCAS; and a washing and recovery step of washing the HPMCAS in the suspension and recovering the washed HPMCAS. Further, there is provided HPMCAS having yellowness at 20° C. of 15.0 or less, as determined in a 2% by mass solution of the HPMCAS in a mixed solvent of dichloromethane, methanol and water in a mass ratio of 44:44:10.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention relates to hydroxypropyl methyl cellulose acetatesuccinate and a method for producing the hydroxypropyl methyl celluloseacetate succinate.

2. Related Art

Hydroxypropyl methyl cellulose acetate succinate (another name:hypromellose acetate succinate; and hereinafter also referred to as“HPMCAS”), which is one of the enteric base materials, is widely usedfor a solid dispersion obtained by hot melt extrusion or spray drying,wherein the HPMCAS is used together with a water-insoluble drug. It isalso widely used for coating to control the release of a drug.

In particular, an enteric coated preparation is one of the importantpreparations and is widely used for administering an acid-labile drug,protecting the gastric mucosa, or the like. In the production of anenteric coated preparation, there is generally used a method comprisingsteps of: dissolving HPMCAS in an organic solvent, and spraying theresulting solution to form an enteric coating on a surface of thepreparation containing a drug. Since such coating is applied to theoutermost surface of the preparation, the coloring of HPMCAS to be usedfor the coating is desirably as small as possible in consideration ofproduction of colored preparations and the visual sensation of thepreparation at the time of taking. In addition, from the viewpoint ofspraying efficiently to form an enteric coated preparation, a solutionof HPMCAS in an organic solvent preferably has a lower viscosity.

An esterified cellulose ether represented by HPMCAS can be produced in aknown manner. For example, an esterified cellulose ether can be producedby a method in which a water-soluble cellulose ether is reacted with anacid anhydride as an esterification agent in an aliphatic carboxylicacid as a solvent in the presence of an alkali metal salt as a catalyst,by using a biaxial kneader (JPH08-333401A).

As an stirring device, a planetary kneader in which a rotating shaft isconnected to an orbitally revolving shaft and a stirring bladesimultaneously rotates around its axis and oribitally revolves in atank, is used for the production of a developing liquid because ofreduction of the dead space in the stirring tank and possible shorteningof the kneading time (see FIGS. 1 to 3 in WO 2018/116658A).

SUMMARY OF THE INVENTION

The HPMCAS produced by the method described in JPH08-333401A is open forimprovement of yellowness and a viscosity when dissolved in an organicsolvent.

The invention has been made in view of the above circumstances, and anobject of the invention is to provide HPMCAS having low yellowness and alow viscosity, and a method for producing the HPMCAS.

As a result of extensive studies to achieve the above object, theinventors have found that HPMCAS having low yellowness and a lowviscosity when dissolved in an organic solvent can be produced by usinga kneader reactor equipped with two or more stirring blades rotatingaround their own axes and orbitally revolving, in an esterification stepin a method for producing the HPMCAS, and has completed the invention.

In an aspect of the invention, there is provided the method forproducing hydroxypropyl methyl cellulose acetate succinate comprising:

an esterification step of reacting hydroxypropyl methyl cellulose withan acetylating agent and a succinoylating agent in the presence of analiphatic carboxylic acid in a knead reactor equipped with two or morestirring blades rotating around their own axes and orbitally revolving,to obtain a reaction product solution containing hydroxypropyl methylcellulose acetate succinate;

a precipitation step of precipitating the hydroxypropyl methyl celluloseacetate succinate by mixing the reaction product solution with water toobtain a suspension of the precipitated hydroxypropyl methyl celluloseacetate succinate; and

a washing and recovery step of washing the hydroxypropyl methylcellulose acetate succinate in the suspension and recovering the washedhydroxypropyl methyl cellulose acetate succinate.

In another aspect of the invention, there is provided hydroxypropylmethyl cellulose acetate succinate having yellowness at 20° C. of 15.0or less, as determined in a 2% by mass solution of the hydroxypropylmethyl cellulose acetate succinate in a mixed solvent ofdichloromethane, methanol and water in a mass ratio of 44:44:10.

According to the invention, there can be produced HPMCAS having lowyellowness and a low viscosity when dissolved in an organic solvent, andthe produced HPMCAS is useful as an enteric coating base material or thelike.

BRIEF EXPLANATION OF DRAWINGS

FIG. 1 is a conceptual cross-sectional view of a kneader reactorequipped with three stirring blades.

FIG. 2 shows a stirring blade connected to a kneader reactor.

FIG. 3 shows an example of a stirring blade having a frame shape of (a)a tetragon, (b) a pentagon, or (c) a twisted tetragon.

FIG. 4 shows examples of (a) a turbine-shaped stirring blade, (b) aribbon-shaped stirring blade, and (c) an anchor-wing-shaped stirringblade.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the esterification step, an esterification reaction of hydroxypropylmethyl cellulose with an acetylating agent and a succinoylating agent iscarried out in the presence of an aliphatic carboxylic acid in a kneaderreactor equipped with two or more stirring blades rotating around theirown axes and orbitally revolving to obtain a reaction product solutioncontaining hydroxypropyl methyl cellulose acetate succinate.

The kneader reactor comprises two or more stirring blades rotatingaround their own axes and orbitally revolving, a rotation part forallowing the stirring blades to rotate on their own, a revolution partfor allowing the stirring blades to orbitally revolve, and a reactionvessel. The rotation part for performing rotational motion is disposedin the revolution part for performing revolutionary motion. The kneaderreactor allows not only stirring by the rotational motion but alsostirring by the revolutionary motion. Such stirring by planetary motionallows the esterification reaction to be carried out while applyingsufficient shearing force to the reaction solution for producing HPMCAS.From the viewpoint of applying adequate shearing force to the reactionsolution for producing HPMCAS, the directions of the rotation andrevolution are preferably opposite to each other.

For example, FIG. 1 shows an embodiment in which three stirring bladesrotating around their own axes and orbitally revolving are provided.FIG. 1 is a conceptual cross-sectional view of a kneader reactor 1equipped with three stirring blades. The rotational axes and therevolutionary axis of the stirring blades are arranged parallel to eachother in the vertical direction. Each arrow indicates a rotationaldirection or a revolutionary direction. Rotational shafts (axes) 7 ofthe stirring blades form rotational tracks 6 of the stirring blades andare arranged at the apexes of the equilateral triangle having a gravitycenter which is also a center 5 of the revolution part 4 for performingthe revolutionary movement. As described above, in the embodiment inwhich three or more stirring blades rotating around their own axes andorbitally revolving are provided, the rotational shafts (axes) of thestirring blades are preferably arranged at the apexes of a regularpolygon having a gravity center which is also a center of the revolutionpart for performing the revolutionary motion. Similarly, in theembodiment in which two stirring blades rotating around their own axesand orbitally revolving are provided, the two rotational shafts (axes)of the stirring blades am preferably arranged at both ends of a straightline having a gravity center which is also a center of the revolutionpart for performing the revolutionary motion.

In the kneader reactor, seal parts for the rotational shafts (axes) andthe revolutionary shaft (axis) of the stirring blades may be placedvertically to the ground surface from the viewpoint of avoidingcontacting with the reaction solution for producing HPMCAS and reducingcorrosion and/or degradation of the shaft seal parts. FIG. 2 shows astirring blade 3 connected to the kneader reactor 1. The rotationalshaft seal part 8 is preferably arranged on the rotational shaft 7 ofthe stirring blade, and the revolutionary shaft seal part 10 ispreferably arranged on the revolutionary shaft 9 of the stirring blade,both seal parts being arranged only in the upper part of the reactor soas not to come into contact with the reaction solution.

The kneader reactor comprises two or more stirring blades. The number ofthe stirring blades is preferably two or more, more preferably 3 to 5,from the viewpoint of sufficient stirring.

Examples of the shape of the stirring blade include frames, turbines,ribbons, and anchor wings. FIG. 3 shows an example of the stirring bladehaving a frame shape of (a) tetragon, (b) pentagon, or (c) twistedtetragon. FIG. 4 shows an example of the stirring blade having a shapeof (a) turbine, (b) ribbon, or (c) anchor-wing.

The stirring blade preferably has a frame shape from the viewpoint ofsufficient stirring. Examples of the frame shape include a tetragon(e.g., a rectangle or a square) having two sides (left and rightvertical sides) vertical to the ground surface and the other two sides(upper and lower horizontal sides) parallel to the ground surface andbeing in contact with the rotational shaft at the center of the upperhorizontal side; a pentagon (such as a home plate of the baseball game)being bent upward at a contact point with a rotational shaft at thecenter of said upper horizontal side of said tetragon; and a twistedtetragon having a structure in which said vertical sides of saidtetragon are twisted, said lower horizontal side forms an angle ofpreferably 10 to 150 with said upper horizontal side, and said upperhorizontal side is in contact with the rotational axis at the center ofthe upper horizontal side. These examples are shown in FIG. 3 (a), FIG.3 (b) and FIG. 3 (c), respectively, where the vertical side is denotedby S_(v), and the horizontal side is denoted by S_(h).

Although not shown in FIG. 3, in the frame shape of the home-plate-likepentagon having the upper horizontal side bent upward at the contactpoint with the rotational shaft, the lower horizontal side may form anangle of preferably 10 to 150° with the imaginary straight upperhorizontal side (i.e., without said bend) obtainable by connecting theupper ends of the two left and right vertical sides. Thus, the twistedpentagon may be included as an example of the frame shape.

The peripheral speed of the rotation of one stirring blade is preferablyfrom 0.010 to 2.000 m/s, more preferably from 0.010 to 0.300 m/s, stillmore preferably from 0.020 to 0.200 m/s, and particularly preferablyfrom 0.040 to 0.155 m/s, from the viewpoint of sufficient stirring.

In the present specification, the “peripheral speed of the rotation ofone stirring blade” is the speed of the fastest part of one stirringblade (i.e., the speed for the outermost periphery of one stirringblade, such as for the rotational track of the stirring blade in FIG. 1)which rotates around its own axis in the kneader reactor. The peripheralspeed v₁ (m/s) of the one stirring blade may be obtained from thediameter d (mm) of one stirring blade and the rotation speed n₁ (rpm) ofthe one stirring blade by the following equation. It is noted that rpmmeans the number of rotations per minute.

V ₁ =π×d×n ₁/60000

The peripheral speed of the revolution of one stirring blade ispreferably from 0.001 to 2.000 m/s, more preferably from 0.001 to 0.500m/s, still more preferably from 0.002 to 0.050 m/s, and particularlypreferably from 0.002 to 0.025 m/s, from the viewpoint of sufficientstirring.

The “peripheral speed of the orbital revolution of one stirring blade”is a speed in a circular orbit drawn by the center of the rotationalshaft of the stirring blade in the kneader reactor. The circumferentialspeed v₂ (m/s) of the rotational shaft of one stirring blade is obtainedfrom the distance r (mm) from the center of the orbital revolution partto the center of the rotational shaft and the revolution speed n₂ (rpm)of the orbital revolution part by the following equation.

V ₂=2×π×r×n ₂/60000

The ratio of the peripheral speed of the rotation to the peripheralspeed of the orbital revolution of one stirring blade is preferably from0.005 to 200, more preferably from 1.0 to 20.0, still more preferablyfrom 1.5 to 15.0, and particularly preferably from 2.0 to 10.0, from theviewpoint of sufficient stirring.

When two or more stirring blades are used, each peripheral speed of therotation may be the same as or different from each other. Examples ofthe kneader reactor comprising two or more stirrings blades for rotationand orbital revolution include a triple arm planetary mixer (Tri-Mixproduced by INOUE MFG., INC.), and a planetary mixer (produced by AsadaIron Works Co., Ltd.).

Hydroxypropyl methyl cellulose (another name: hypromellose; hereinafteralso referred to as “HPMC”) is a non-ionic water-soluble celluloseether. HPMC synthesized by a known method, or commercially availableHPMC may be used.

The degree of substitution (DS) of the methoxy groups of HPMC ispreferably from 1.10 to 2.20, more preferably from 1.40 to 2.00, andstill more preferably from 1.60 to 2.00, from the viewpoint of obtainingHPMC having the reduced number of undissolved fibers. The molarsubstitution (MS) of the hydroxypropoxy groups of HPMC is preferablyfrom 0.10 to 1.00, more preferably from 0.20 to 0.80, and still morepreferably from 0.2 to 0.65, from the viewpoint of obtaining HPMC havingthe reduced number of undissolved fibers.

It is noted that with respect to HMPC, the DS of the methoxy groupsmeans a degree of substitution of the methoxy groups, i.e., an averagenumber of methoxy groups per anhydroglucose unit, and the MS of thehydroxypropoxy groups means a molar substitution of the hydroxypropoxygroups, i.e., an average number of moles of hydroxypropoxy groups permole of anhydroglucose. The DS of the methoxy groups and the MS of thehydroxypropoxy groups of HPMC may be determined by converting the valuesobtained by the measurement in accordance with the JapanesePharmacopoeia Seventeenth Edition.

The viscosity at 20° C. of HPMC, as determined in a 2% by mass aqueoussolution thereof, is preferably from 1.0 to 50.0 mPa·s, more preferablyfrom 2.0 to 20.0 mPa·s, from the viewpoint of kneadability in theesterification step.

The viscosity at 20° C. of a 2% by mass aqueous solution of HPMC may bedetermined in accordance with the viscosity measurement by capillarytube viscometer under “Viscosity Determination” in “General Tests” ofthe Japanese Pharmacopoeia, Seventeenth Edition.

Examples of the aliphatic carboxylic acid include an aliphaticcarboxylic acid having 2 to 4 carbon atoms such as acetic acid,propionic acid and butyric acid. The acetic acid is preferred from theviewpoint of economy.

The amount of the aliphatic carboxylic acid to be used is preferablyfrom 3.00 to 10.00 mol, more preferably from 4.00 to 8.00 mol, relativeto 1 mol of HPMC from the viewpoint of dissolving HPMC and increasingthe reaction rate.

Examples of the acetylating agent include acetic anhydride and acetylchloride. The acetic anhydride is preferred from the viewpoint ofeconomy.

The amount of the acetylating agent to be used is not particularlylimited as long as HPMCAS having the desired degree of substitution isobtained. It is preferably from 0.20 to 1.50 mol, more preferably from0.40 to 1.30 mol, relative to 1 mol of HPMC from the viewpoint ofreaction efficiency.

Examples of the succinoylating agent include succinic anhydride andsuccinyl chloride. The succinic anhydride is preferred from economy.

The amount of the succinoylating agent to be used is not particularlylimited as long as HPMCAS having the desired degree of substitution isobtained. It is preferably from 0.10 to 1.50 mol, more preferably from0.20 to 1.20 mol, relative to 1 mol of HPMC from the viewpoint ofreaction efficiency.

The esterification reaction may be carried out in the presence of acatalyst. As the catalyst, an alkali metal carboxylate such as sodiumacetate is preferred from the viewpoint of economy. The catalyst may beused singly or in combination of two or more as needed. A commerciallyavailable catalyst may be used.

The amount of the catalyst to be used may be selected in considerationof the degree of substitution of HPMCAS. It is preferably from 0.10 to2.00 mol, more preferably from 0.30 to 1.90 mol, relative to 1 mol ofHPMC from the viewpoint of reaction efficiency.

The reaction temperature in the esterification step is preferably from60 to 120° C., more preferably from 60 to 100° C., from the viewpoint ofthe reaction rate.

The reaction time in the esterification step is preferably from 2 to 8hours, more preferably from 3 to 6 hours, from the viewpoint ofobtaining HPMCAS having the desired degree of substitution.

Next, the reaction product solution containing HPMCAS is mixed withwater to obtain a suspension of precipitated HPMCAS in the precipitationstep.

The temperature of the water is preferably from 5 to 40° C. from theviewpoint of controlling the diameters of HPMCAS particles in thesuspension. The mass of the water is preferably 3.3 to 8.5 times, morepreferably 3.8 to 6.5 times the mass of the reaction product solution,from the viewpoint of controlling the diameters of HPMCAS particles inthe suspension.

The mixing of the reaction product solution containing HPMCAS with thewater is not particularly limited and may be carried out by aconventional method.

After the precipitation step, the HPMCAS in the suspension is washed andrecovered in the wash and recovery step.

According to the invention, since hydroxypropyl methyl cellulose acetatesuccinate having low yellowness and a low viscosity when dissolved in anorganic solvent can be produced by using a kneader reactor comprisingtwo or more stirring blades which rotate around their own axes andorbitally revolve in an esterification step of the HPMCAS productionmethod, a washing method is not particularly limited. The washing withwater is preferred from the viewpoint of removing free acetic acid andfree succinic acid from the HPMCAS.

The method of washing with water is not particularly limited. Examplesof the method of washing with water include a method comprising stepsof: separating crude HPMCAS from a suspension through centrifugation,filtration, decantation or the like, then resuspending the obtainedcrude HPMC in water, while stirring with a stirrer, and subjecting theobtained suspension to centrifugation, filtration or the like to removethe water used for washing; a method comprising a step of continuouslypouring water into the above-obtained crude HPMCAS; and a methodcomprising a step of washing HPMCAS in a suspension by repeatedlyreplacing a portion of a liquid in the suspension with water.

The recovered HPMCAS may be subjected to an optional drying step toobtain dried HPMCAS. The drying temperature in the drying step ispreferably from 60 to 100° C., more preferably from 70 to 80° C., fromthe viewpoint of preventing aggregation of HPMCAS. The drying time inthe drying step is preferably from 1 to 5 hours, more preferably from 2to 3 hours, from the viewpoint of preventing aggregation of HPMCAS.

The yellowness at 20° C. of a 2% by mass solution of hydroxypropylmethyl cellulose acetate succinate in a mixed solvent ofdichloromethane, methanol and water in a mass ratio of 44:44;10 ispreferably 15.0 or less, more preferably 0.1 to 13.0. When theyellowness is greater than 15.0, the reduction in coloring in the coatedpreparation containing HPMCAS may not be satisfactory.

It is noted that the yellowness may be measured at 20° C. by providing a2% by mass solution of HPMCAS in a mixed solvent of dichloromethane,methanol and water in a mass ratio of 44:44:10 as a sample formeasurement, and analyzing the sample by using a direct readingtri-stimulus color computer such as an SM color computer SM-4 (producedby Suga Test Instruments Co., Ltd.).

The viscosity at 20° C. of a 2% by mass solution of hydroxypropyl methylcellulose acetate succinate in a mixed solvent of dichlormethane andmethanol in a mass ratio of 50:50 is preferably 140 mPa-s or less, morepreferably from 80 to 130 mPa·s, from the viewpoint of increasing theconcentration of HPMCAS in the coating solution.

It is noted that the viscosity may be measured using a Brookfieldviscometer in accordance with the Viscosity Determination in theJapanese Pharmacopoeia Seventeenth Edition.

The DS of the methoxy groups of HPMCAS is preferably from 1.10 to 2.20,more preferably from 1.40 to 2.00, and still more preferably from 1.60to 2.00.

The MS of the hydroxypropoxy groups of HPMCAS is preferably from 0.10 to1.00, more preferably from 0.20 to 0.80, and still more preferably from0.20 to 0.65.

The DS of the acetyl groups of HPMCAS is preferably from 0.10 to 2.50,more preferably from 0.10 to 1.00, and still more preferably from 0.20to 0.80.

The DS of the succinyl groups of HPMCAS is preferably from 0.10 to 2.50,more preferably from 0.10 to 1.00, and still more preferably from 0.10to 0.60.

The ratio of the DS of the acetyl groups to the DS of the succinylgroups of HPMCAS (acetyl group/succinyl group) is preferably from 0.50to 4.00, more preferably from 0.80 to 3.70, from the viewpoint ofsolubility.

It is noted that with respect to HPMCAS, the DS of the methoxy groups,the DS of the acetyl groups, and the DS of the succinyl groups meanrespective degrees of substitutions, i.e., an average number of methoxygroups per anhydroglucose unit (AGU), an average number of acetyl groupsper AGU, and an average number of succinyl groups per AGU, and the MS ofthe hydroxypropoxy groups means a molar substitution, i.e., an averagenumber of moles of hydroxypropoxy groups per mole of anhydroglucose.

It is noted that the DS of the methoxy groups, the DS of the acetylgroups, the DS of the succinyl groups, and the MS of the hydroxypropoxygroups of HPMCAS may be converted from the values obtained by the methodin “Hypromellose Acetate Succinate” under the Official Monographs of theJapanese Pharmacopoeia Seventeenth Edition.

EXAMPLES

Hereinafter, the invention will be described in detail with referencewith Examples and Comparative Example. It should not be construed thatthe invention is limited by or to them.

Example 1

In a 5L vertical kneader reactor (Tri-Mix TX-5 produced by INOUE MFG.,INC.) equipped with three frame-shaped stirring blades (twisted pentagonhaving an angle of 90°, made of SCS16, produced by INOUE MFG., INC.)which could rotate around their own axes and orbitally revolve, 1120 gof glacial acetic acid was placed. The 700 g of HPMC having the DS ofthe methoxy groups of 1.87, the MS of the hydroxypropoxy groups of 0.24,and the viscosity at 20° C. of 3.2 mPa·s, as determined in a 2% by massaqueous solution, 396.7 g of acetic anhydride, 141.8 g of succinicanhydride, and 338.4 g of sodium acetate were added therein to carry outthe esterification reaction at 85° C. for 5 hours.

The peripheral speed of the rotation of each frame-shaped stirring bladewas 0.050 m/s, the peripheral speed of the orbital revolution was 0.019m/s, and the ratio of the peripheral speed of the rotation to theperipheral speed in the orbital revolution was 2.6. Thus, the peripheralspeed of the rotation was the same in all of three frame-shaped stirringblades which rotated around their own axes and orbitally revolved. Inthe same manner as in FIG. 1, the rotational axes of the threeframe-shaped stirring blades which rotated and orbitally revolved wasarranged at the apexes of the equilateral triangle having a gravitycenter which was also a center of the revolutionary part for performingrevolutionary motion. Each of the three frame-shaped stirring blades forrotation and orbital revolution is in a form of twisted pentagon, havingtwo sides, left and right, vertical to the ground surface (i.e., leftand right vertical sides), a side parallel to the ground surface (i.e.,lower horizontal side), and two sides formed by bending the upperhorizontal side upward at a central contact point with the rotationalaxis as shown in FIG. 3 (b), and having a structure twisted at thecenter of the vertical sides so as to make the lower horizontal sidetwisted by 90° with respect to the imaginary straight upper horizontalside (without bending) obtainable by connecting the upper ends of theleft and right vertical sides. The length of the lower horizontal side(diameter) was 96 mm. The peripheral speed of the rotation was adjustedby setting the rotation speed to 10 rpm. The peripheral speed of therevolution was adjusted by setting the distance from the center of therevolution part for revolutionary motion to the center of eachrotational shaft (i.e., the distance from the gravity center of theequilateral triangle to each apex of the equilateral triangle) to 57.7mm and the revolution speed to 3.1 rpm. The axes of rotation and theaxis of revolution of the stirring blades were arranged perpendicularlyto the ground surface. In the same manner as in FIG. 2, the sealed partsof the shafts of rotation and revolution were arranged so as to belocated only in the upper parts of the reactor for avoiding the contactwith the reaction solution. In addition, the directions of the rotationswere opposite to the direction of the orbital revolution.

Water of 20° C. having a mass of 5.0 times the mass of the obtainedreaction product solution containing HPMCAS was gradually added to thereaction product solution to obtain a suspension of precipitated HPMCAS.The precipitated HPMCAS was filtered on an 80 mesh sieve to obtain crudeHPMCAS. The obtained crude HPMCAS was washed by repeating the followingprocess five times. The process comprised re-suspension of crude HPMCASin water of 20° C. having a mass of 10 times the mass of starting HPMC,stirring for 10 minutes, and then filtration on an 80 mesh sieve. As aresult, washed HPMCAS was obtained. Finally, the washed HPMCAS was driedat 80° C. for 3 hours to obtain HPMCAS.

The reaction conditions in the esterification step, and the degrees ofsubstitutions, yellowness and viscosity of the obtained HPMCAS are shownin Table 1

Example 2

HPMCAS was obtained in the same manner as in Example 1 except that theratio of each peripheral speed of the rotation to the peripheral speedof the orbital revolution of the stirring blades which rotated aroundtheir own axes and orbitally revolved in the esterification reaction wasset to 3.9 by setting the rotation speed to 15 rpm.

The reaction conditions in the esterification step, and the degrees ofsubstitutions, yellowness and viscosity of the obtained HPMCAS are shownin Table 1.

Example 3

HPMCAS was obtained in the same manner as in Example 1 except that theratio of each peripheral speed of the rotations to the peripheral speedof the orbital revolution of the stirring blades which rotated andorbitally revolved in the esterification reaction was set to 7.9 bysetting the rotation speed to 30 rpm.

The reaction conditions in the esterification reaction step, and thedegrees of substitutions, yellowness and viscosity of the obtainedHPMCAS are shown in Table 1.

Comparative Example 1

In a 5L lateral kneader reactor (PNV-5T produced by IRIE SHOKAI Co.,Ltd.) equipped with biaxial stirring blades (Z-shaped stirring bladesfor PNV-5T, made of SUS316L, produced by IRIE SHOKAI Co., Ltd.), 1376 gof glacial acetic acid was placed. The 860 g of HPMC having the DS ofthe methoxy groups of 1.87, the MS of the hydroxypropoxy groups of 0.24,and the viscosity at 20° C. of 3.2 mPa-s, as determined in a 2% by massaqueous solution, 487.3 g of acetic anhydride, 174.2 g of succinicanhydride, and 415.7 g of sodium acetate were added therein to carry outthe esterification reaction at 85° C. for 5 hours.

The Z-shaped stirring blades were used as the stirring blades, and eachperipheral speed of the rotation around its own axis was 0.18 m/s. Theperipheral speed of the rotation was adjusted by setting the diameter ofthe stirring blade to 80 mm and the rotation speed to 43 rpm.

Water of 20° C. having a mass of 5.0 times the mass of the obtainedreaction product solution containing HPMCAS was gradually added to thereaction product solution to obtain a suspension of precipitated HPMCAS.The precipitated HPMCAS was filtered on an 80 mesh sieve to obtain crudeHPMCAS. The obtained crude HPMCAS was washed by repeating the followingprocess five times. The process comprised re-suspension of crude HPMCASin water of 20° C. having a mass of 10 times the mass of starting HPMC,stirring for 10 minutes, and then filtration on an 80 mesh sieve. As aresult, washed HPMCAS was obtained. Finally, the washed HPMCAS was driedat 80° C. for 3 hours to obtain HPMCAS.

The reaction conditions in the esterification step, and the degrees ofsubstitutions, yellowness and viscosity of the obtained HPMCAS are shownin Table 1

TABLE 1 reagents used for esterification reaction HPMC *1 acetic acidacetic anhydride succinic anhydride sodium acetate MeO HPO viscosity(mol/mol (mol/mol (mol/mol (mol/mol groups DS groups MS (mPa · s) (g)(mol) (g) HPMC) (g) HPMC) (g) HPMC) (g) HPMC) Example1 1.87 0.24 3.2 7003.46 1120 5.38 396.7 1.12 141.8 0.41 338.4 1.19 Example2 1.87 0.24 3.2700 3.46 1120 5.38 396.7 1.12 141.8 0.41 338.4 1.19 Example3 1.87 0.243.2 700 3.46 1120 5.38 396.7 1.12 141.8 0.41 338.4 1.19 Comp.Ex.1 1.870.24 3.2 860 4.26 1376 5.38 487.3 1.12 174.2 0.41 415.7 1.19 *1 “MeOgroups” mean methoxy groups, “HPO groups” mean hydroxypropoxy groups,and “viscosity” means a viscosity at 20° C. as determined in a 2% bymass aqueous solution.

TABLE 2 reaction conditions for esterification product HPMCAS *1peripheral peripheral speed reaction reaction MeO HPO Ac Suc speed (A)of (B) of orbital temp. time groups groups groups groups viscosityrotation (m/s) revolution (m/s) A/B (° C.) (hr) DS MS DS DS Ac/Sucyellowness (mPa · s) Example1 0.050 0.019 2.6 85 5 1.88 0.24 0.50 0.311.61 11.1 103.5 Example2 0.075 0.019 3.9 85 5 1.87 0.24 0.51 0.31 1.6511.4 104.3 Example3 0.151 0.019 7.9 85 5 1.89 0.24 0.58 0.31 1.87 11.2103.6 Comp.Ex.1 0.180 — — 85 5 1.90 0.24 0.57 0.30 1.90 18.8 147.2 *1“MeO groups” mean methoxy groups, “HPO groups” mean hydroxypropoxygroups, “Ac groups” mean acetyl groups. “Suc groups” mean succinylgroups, “yellowness” means yellowness at 20° C. as determined in a 2% bymass solution of HPMCAS in a mixed solvent of dichloromethane, methanoland water in a mass ratio of 44:44:10, and “viscosity” means a viscositymeasured at 20° C. in a 2% by mass solution of HPMCAS in a mixed solventof dichloromethane and methanol in a mass ratio of 50:50.

HPMCAS produced in each of Examples 1 to 3 by subjection to theesterification step in the kneader reactor equipped with a plurality ofstirring blades which rotated around their own axes and orbitallyrevolved, was lower in yellowness and the viscosity than HPMCAS producedin Comparative Example 1 by subjection to the esterification step in thelateral kneader reactor equipped with the biaxial stirring blades whichrotated around the axes.

1. A method for producing hydroxypropyl methyl cellulose acetatesuccinate comprising: an esterification step of reacting hydroxypropylmethyl cellulose with an acetylating agent and a succinoylating agent inthe presence of an aliphatic carboxylic acid in a kneader reactorequipped with two or more stirring blades rotating around their own axesand orbitally revolving, to obtain a reaction product solutioncontaining hydroxypropyl methyl cellulose acetate succinate; aprecipitation step of precipitating the hydroxypropyl methyl celluloseacetate succinate by mixing the reaction product solution with water toobtain a suspension of the precipitated hydroxypropyl methyl celluloseacetate succinate; and a washing and recovering step of washing thehydroxypropyl methyl cellulose acetate succinate in the suspension andrecovering the washed hydroxypropyl methyl cellulose acetate succinate.2. The method for producing the hydroxypropyl methyl cellulose acetatesuccinate according to claim 1, wherein a shape of each of the stirringblades is selected from the group consisting of a frame, a turbine, aribbon, and an anchor wing.
 3. Hydroxypropyl methyl cellulose acetatesuccinate having yellowness at 20° C. of 15.0 or less, as determined ina 2% by mass solution of the hydroxypropyl methyl cellulose acetatesuccinate in a mixed solvent of dichloromethane, methanol and water in amass ratio of 44:44:10.